Method for preparing acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

Abstract

The present invention relates to a method for preparing an acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula (IIa) by optical resolution of a compound of formula (II) using a hydrolase. The present invention also relates to a method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises optical resolution of a compound of formula (II) using a hydrolase. The present invention further relates to the use of a hydrolase in the method for preparing a compound of formula (IIa).

Description

[Technical Field]

[0001] The present invention relates to a method for preparing the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula (IIa) by optical resolution of the compound of formula (II) using a hydrolase. [ka]

[0002] The present invention also relates to a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the optical resolution of the compound of formula (II) using a hydrolase.

[0003] The present invention further relates to a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises reacting a racemic acid of formula (III) with a haloester of general formula (V) to obtain the racemic (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula (II). the latter is converted by optical resolution with a hydrolase into the enantiomeric acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula (IIa), the latter is hydrolyzed to a compound of formula (IIIa), and then the compound of formula (IIIa) is converted to a compound of formula (Ia). [ka]

[0004] More particularly, the present invention provides a compound of formula (IIa) [ka] (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, ... Formula (II) [ka] wherein R is a linear or branched C1-C25 chain.

[0005] The present invention more particularly relates to a compound of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0006] The present invention further relates to the use of a hydrolase in a process for preparing a compound of formula (IIa).

[0007] The present invention also relates to the use of a hydrolase in a method for preparing a compound of formula (Ia). The term "finerenone" refers to the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, or the compound of formula (Ia) [ka] The present invention relates to the compound

[0008] Formula (I) [ka] The compound is a racemic form of finerenone.

[0009] The phrase "enantiomers of finerenone" or "enantiomers of compounds of formula (I)" refers to compounds of formula (Ia) and (Ib) [ka] The present invention relates to the compound

[0010] Finerenone (Ia) acts as a nonsteroidal antagonist of the mineralocorticoid receptor and can be used as a drug for preventing and / or treating cardiovascular and renal disorders, such as heart failure and diabetic nephropathy. [Background technology]

[0011] The compound of formula (Ia) and its preparation method are described in WO 2008 / 104306 and ChemMedChem 2012, 7, 1385, and also in WO 2016 / 016287. To reach the compound of formula (Ia), a racemic mixture of amides (I) [ka] The enantiomers (Ia) and (Ib) [ka] This is because the compound of formula (Ia) [ka] This is because only the enantiomer of is active.

[0012] In a published research-scale synthesis (WO 2008 / 104306), N-(dicyclopropylmethyl)-N 2A specially synthesized chiral phase containing α-methacryloyl-D-leucine amide was used for this purpose (prepared in-house). It was found that separations could also be performed with readily available commercially available phases: Chiralpak® AS-V phase, 20 μm. The eluent used was a 60:40 mixture of methanol / acetonitrile. In this case, chromatography can be performed on conventional chromatography columns, but techniques known to those skilled in the art, such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68) or Varicol® (Computers and Chemical Engineering 27 (2003) 1883-1901), are preferred. [ka]

[0013] While SMB separations offer relatively good yields and optical purity, procuring and operating such equipment under GMP conditions poses significant challenges and is costly. Even the chiral phases used each time are very expensive, have a limited lifespan, and must be replaced multiple times during production. For production technology reasons, this is not optimal unless a second facility is available to ensure continuous operation, which entails additional costs. Furthermore, especially for products produced on a ton-scale, solvent recovery is a time-critical step, requires the procurement of large falling-film evaporators, and consumes enormous amounts of energy.

[0014] The challenge addressed was therefore to provide an alternative synthetic route to enantiomerically pure finerenone (Ia) that is significantly cheaper and can be carried out using conventional pilot plant equipment (stirred tank / isolation equipment). Such equipment is conventionally standard for pharmaceutical manufacturing plants and does not require additional investment. Furthermore, the qualification and validation of batch processes is significantly easier than for chromatographic processes, which is an additional advantage. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Publication No. 2008 / 104306 Brochure [Patent Document 2] International Publication No. 2016 / 016287 Brochure [Non-patent literature]

[0016] [Non-Patent Document 1] ChemMedChem 2012, 7, 1385 [Non-patent document 2] G.Paredes, M.Mazotti, Journal of Chromatography A, 1142(2007):56~68 [Non-patent document 3] Computers and Chemical Engineering 27(2003)1883~1901 Summary of the Invention [Means for solving the problem]

[0017] The present invention relates to a compound of formula (IIa) [ka] wherein R is a linear or branched C1-C25 chain, to the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, (II) [ka] wherein R is a linear or branched C1-C25 chain.

[0018] The expression "C1 to C25 chain" means "C1 to C 25 "C1~C alkyl chain" 25 The term "alkyl" means a straight or branched chain saturated monovalent hydrocarbyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 carbon atoms. Examples of alkyl groups that can be used according to the present invention are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl groups, or isomers thereof.

[0019] The C1 to C25 chain may be a straight chain or a branched chain.

[0020] The C1 to C25 chain may be substituted with an aromatic group.

[0021] The term "substituted" means that one or more hydrogen atoms on the atom or group in question have been replaced with one selected from a specified group, provided that the replacement does not exceed the normal valence of the atom in question under the particular circumstances. Combinations of substituents and / or variables are permissible.

[0022] The term "unsubstituted" means that none of the hydrogen atoms have been replaced.

[0023] The term "aromatic group" encompasses "aryl" and "heteroaryl."

[0024] The term "aryl" is understood to mean a monovalent, aromatic or partially aromatic, mono-, bi- or tricyclic hydrocarbon ring ("C6-C14 aryl"), preferably having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9 aryl"), such as an indanyl or indenyl group, or a ring having 10 carbon atoms ("C10 aryl"), such as a tetralinyl, dihydronaphthyl, or naphthyl group, or a biphenyl group ("C12 aryl"), or a ring having 13 carbon atoms ("C13 aryl"), such as a fluorenyl group, or a ring having 14 carbon atoms ("C14 aryl"), such as an anthracenyl group. The aryl group is preferably a phenyl group.

[0025] The term "heteroaryl" is understood to mean a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system, preferably having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5- to 14-membered heteroaryl" group), in particular 5 or 6 or 9 or 10 atoms, containing at least one heteroatom, which may be the same or different, this heteroatom being oxygen, nitrogen or sulfur, and which in each case may also be benzo-fused. More particularly, heteroaryl is thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthopyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.

[0026] A "hydrolase" is an enzyme that hydrolytically cleaves an ester, ether, peptide, glycoside, acid anhydride, or C-C bond in a reversible reaction. The term is used in the sense commonly understood by those skilled in the art. Further examples of hydrolases are listed below. The term "hydrolase" encompasses "lipases," "esterases," "amidases," and "proteases."

[0027] "Lipases," "esterases," "amidases," and "proteases" are subgroups of hydrolases. These terms are used in the conventional sense by those skilled in the art. Further examples of lipases are listed below.

[0028] In the novel process of the present invention, a racemic mixture of amides (I) [ka] Instead of the complex SMB separation described above into the enantiomers of formula (Ia) and (Ib), the synthetic precursor, i.e., the racemic unit (II) [ka] The advantageous enzymatic resolution of

[0029] The reaction of racemic dihydropyridine esters with hydrolases, preferably lipases, for optical resolution has been described in the literature. Examples include Torres et al., Org.Biomol.Chem., 2017, 15, 5171-5181; Xin et al., China Patent No. 2016-106279000; Verdecia et al., US Patent Application Publication No. 2014 / 0275042; Torres et al., Tetrahedron 71 (2015) 3976-3984; Sobolev et al., Biocatalysis and Biotransformations, 2004, 231-252 (Review); Schnell et al., J.Chem.Soc., Perkin Trans.1-2000-4389.

[0030] Resolution of other substrates is further described in: Tetrahedron Letters, Vol. 29, No. 36, 1988, pp. 4623-4624; Biotechnology Letters, September 1994, Vol. 16, No. 9, pp. 919-922.

[0031] Numerous attempts have been made to synthesize suitable chiral derivatives that can be used in the synthesis of finerenone (Ia) using enzymatic methods. The derivatives described herein are notable for their extremely low solubility in water (significantly less than 100 mg / L) or in water-miscible organic solvents. Therefore, it was quite surprising for those skilled in the art to be able to find conditions that allow the preparation of the chiral acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (IIa) in good yield and high enantiomeric purity.

[0032] Two cases of enzymatic hydrolysis must be distinguished: first, the target enantiomer (IIa) with 4S configuration is hydrolyzed and converted to the acid (IIIa), which is then separated, or second, the enantiomer (IIb) with 4R configuration is hydrolyzed, leaving the ester (IIa) with 4S configuration in solution, which is then later converted to the acid (IIIa) after separation. [ka]

[0033] Both products, ester and acid, can be very easily separated from each other by extraction.

[0034] The conversion can be carried out using the following commercially available enzymes: AK lipase from Pseudomonas fluorescens [CAS number 9001-62-1; preferably UniProtKB entry Q7WZT7 (Sigma-Aldrich, Amano Enzymes)] Type VII lipase from Candida rugosa (Sigma-Aldrich, L 1754) Lipase from Candida rugosa (Sigma-Aldrich 62316) Amano lipase M from Mucor javanicus (Sigma-Aldrich 534803) Amano lipase PS from Burkholderia cepacia (Sigma-Aldrich 534641) Amano Lipase PS-IM (Sigma-Aldrich 709603) Lipase from Aspergillus niger (Sigma-Aldrich 62301) Lipase from Thermomyces lanuginosus (Sigma-Aldrich L 0777) Lipase from Rhizomucor miehei (Sigma-Aldrich L 4277) Lipase from Candida antarctica B (Lipozyme®, Novozymes) Lipase from Candida antarctica A (Novocor® AD L, Novozymes) Lipase from Aspergillus oryzae (Resinase® HT, Novozymes) Lipase from Humicola insolens (Novozym® 51032, Novozymes) Immobilized lipase from Candida antarctica B (Novozym 435, Novozymes) Immobilized lipase from Thermomyces lanuginosus (Lipozyme TL IM, Novozymes) Immobilized lipase from Rhizomucor miehei (Novozym 40086, Novozymes) Lipase from Candida antarctica (Sigma-Aldrich L 4777) in acrylic resin Porcine liver lipase (Sigma-Aldrich E 3019)

[0035] The conversion is carried out in a monophasic or biphasic system using an aqueous buffer solution, such as sodium phosphate or potassium phosphate, preferably potassium phosphate, and a water-miscible or water-immiscible organic solvent, such as ethanol, methanol, n-butanol, isopropanol, acetone, THF, DMF, DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, 2-methyl-THF, toluene, or a mixture thereof. The conversion is carried out at a pH of 7.0 to 10, preferably 7 to 8, more preferably 7. The pH can be maintained constant by sufficient buffering capacity or by the gradual dropwise addition of an inorganic base, such as KOH or NaOH, both in aqueous solution. In some cases, it has been found advantageous to add additives, such as sugars, glycerin, magnesium salts, or calcium salts.

[0036] The conversion is carried out at a temperature between 22 and 45° C., preferably between 25 and 38° C. The mixture is stirred for 10 hours to 10 days (depending on the enzyme used).

[0037] The following solvent combinations have been found to be particularly useful: 2-Methyl-THF / potassium phosphate buffer solution pH 7 10% DMSO / 90% 50mM potassium phosphate buffer pH 7 20% tert-butyl methyl ether / 80% 50mM potassium phosphate buffer, pH 7 Water saturated tert-butyl methyl ether / various buffer solutions pH 7~pH 7.5 50% cyclopentyl methyl ether / 50% 50mM potassium phosphate buffer, pH 7 1:1 w / w Triton® X-100, 1.5% DMF / 98.5% 50 mM potassium phosphate buffer pH 7-8 Water saturated 1,4-dioxane / various buffer solutions pH 7-7.5

[0038] For workup of the reaction solution, the reaction can be stopped by adding saturated sodium chloride solution (or another salt solution, for example, CaCl2), and the product can then be extracted by extraction with a suitable solvent. The product can be further purified by chromatography. In many cases, the crude product can also be directly recrystallized. In this way, it is generally found to be advantageous to recrystallize the product (which generally exhibits an ee% value of more than 70%) once more to obtain an ee% value of more than 99%. A useful solvent for the final recrystallization has been found to be a mixture of tert-butyl methyl ether and an alcohol, such as ethanol, methanol, isopropanol, or ethyl acetate or isopropyl acetate.

[0039] The present invention further provides a compound of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, By optical resolution using hydrolase, a compound of formula (IIa) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0040] Further conversion of the chiral acyloxymethyl ester (IIa) to finerenone (Ia) is described below.

[0041] Starting from the chiral acyloxymethyl ester (IIa or IIb), the acid (IIIa or IIIb) is obtained by alkaline hydrolysis followed by acid workup. [ka]

[0042] The hydrolysis can be carried out in an organic solvent or in a water-miscible solvent using an inorganic base in a manner known per se by methods known to those skilled in the art. It has been found that this reaction can be carried out very easily in a relatively concentrated form in a THF / water mixture. For this purpose, it is preferable to work in a 2:1 THF / water mixture (9 volumes) while metering in aqueous sodium hydroxide at 0-5°C, and then stirring the mixture for 1-2 hours at 0-5°C. Potassium hydroxide solution can also be used, but sodium or potassium hydroxide is preferred. Workup is carried out by extraction with MTBE (methyl tert-butyl ether) and ethyl acetate, or with toluene alone, followed by isolation by adjusting the pH to 7 with a mineral acid, such as hydrochloric acid, sulfuric acid, or phosphoric acid, preferably hydrochloric acid. A saturated solution of the ammonium salt of the corresponding acid, preferably ammonium chloride, can then be added, causing quantitative crystallization of the product. After isolation, the product is washed with water and ethyl acetate, acetonitrile, or acetone, preferably acetonitrile, and dried under vacuum at 40-50°C. The yield is virtually quantitative (99%).

[0043] The subsequent conversion of the acid (IIIa or IIIb) to the amide (Ia or Ib) is described as follows: It has been found that in the conversion of the acid (IIIa or IIIb) in THF, the amide (Ia or Ib) can be crystallized directly from solution and obtained in high yield and purity. To this end, the carboxylic acid (IIIa or IIIb) is reacted with 1.1-1.6 equivalents, preferably 1.3-1.4 equivalents, of 1,1'-carbodiimidazole in THF under DMAP catalysis (5-15 mol%, preferably 10 mol%; in some cases, it has been found that the reaction can be carried out without the addition of DMAP) to give the imidazolide. This is carried out at temperatures between 20 and 50 °C; the preferred approach has been found to be to start at 20 °C, then stir at this temperature for 1-2 hours, followed by further stirring at 50 °C for 2-3 hours. After activation is complete, 3 to 8 equivalents, preferably 4.5 equivalents, of hexamethyldisilazane are added, and the mixture is boiled under reflux for 16 to 24 hours, preferably 16 hours. While the disilylamide compound formed here can optionally be isolated, it has been found to be more advantageous to continue the reaction as a one-pot process. Therefore, after the reaction is complete, the mixture is cooled to 0 to 3°C, and a mixture of water and / or THF is added. It has been found to be advantageous to use 0.5 to 0.7 times the amount of water (relative to the reactants), with 0.52 times the amount being particularly advantageous. Water can be added directly or in a mixture with approximately 1 to 2 volume equivalents of THF. After quenching is complete, the mixture is heated to reflux for a total of 1 to 3 hours, preferably 1 hour. The mixture is cooled to 0°C and stirred at this temperature for 1 to 5 hours, preferably 3 hours. The product is then isolated by filtration or centrifugation. The product is washed with THF and water and dried under vacuum at elevated temperatures (30 to 100°C, preferably 40 to 70°C). The yields are very high, generally exceeding 93% of the theoretical value. The purity is generally greater than 99% (HPLC, 100% method). Compound (Ia) can also be obtained directly by reaction with ammonia gas in an autoclave (approximately 25-30 bar). For this purpose, the preactivation described above is carried out, and the reaction mixture is then heated under pressure under gaseous ammonia. Once the reaction is complete, it is cooled and the product is filtered off.The yields and purities thus obtained are comparable. [ka]

[0044] Final crystallization method (establishment of final variant Mod A): For this purpose, for GMP reasons, (Ia) is first dissolved in ethanol and subjected to particle filtration. The solvent is then distilled off under reduced pressure or at standard temperature; however, toluene-denatured ethanol is preferred. The mixture is concentrated to approximately 1 / 3 to 1 / 5 of its volume, causing the product to crystallize. The mixture is cooled to 0°C, and the crystals are then isolated and dried under vacuum at 40-50°C. Yields are generally greater than 90% of theoretical. The achieved chemical purity is greater than 99.8%, and the content of approximately 100% corresponds to the standard for commercial products according to ICH guidelines. Residual solvents are less than 0.02% in the case of ethanol. The optical purity is significantly greater than 99% ee.

[0045] The non-inventive method described herein features several advantages over the prior art. No special equipment (e.g., SMB, chiral chromatography) is required to separate the enantiomers at the precursor stage of finerenone synthesis (Ia). The enzymatic resolution can be carried out entirely in a conventional stirred reactor. The use of water as the reaction medium saves costs associated with expensive solvents. Consequently, waste disposal is also more environmentally friendly than previous methods. Enzymatic resolution typically yields intermediate (IIa) with an enantiomeric excess (ee%) of 70-91%. Relatively simple crystallization can increase the enantiomeric excess to over 99% ee. Because the incorrect enantiomer is lost in downstream synthetic procedures as a result of crystallization, it is known that even material with a 93% ee can yield highly pure finerenone (Ia). Therefore, to keep losses as low as possible, the ester (IIa) can be recrystallized in a relatively intensive operating mode. DETAILED DESCRIPTION OF THE INVENTION

[0046] Further embodiments of the present invention are described below. The present invention relates to a compound of formula (IIa) [ka] (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, ... (II) [ka] wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group.

[0047] In the context of the present invention, compounds of formula (IIa) [ka] (wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group), the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with a lipase to form a (II) [ka] A preferred method is to prepare the compound by optical resolution of (wherein R is a linear or branched C1 to C25 chain which may be substituted with an aromatic group).

[0048] In the context of the present invention, compounds of formula (IIa) [ka] (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, ... (II) [ka] A preferred method is to prepare the compound by optical resolution of (wherein R is a linear or branched C1 to C25 chain which may be substituted with an aromatic group).

[0049] In the context of the present invention, compounds of formula (IIa) wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with a hydrolase to form (II) wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. The method for preparing the compound by optical resolution of the formula (I) is preferred.

[0050] In the context of the present invention, compounds of formula (IIa) wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid using lipase. (II) wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. The method for preparing the compound by optical resolution of the formula (I) is preferred.

[0051] In the context of the present invention, compounds of formula (IIa) wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid was purified by using AK lipase derived from Pseudomonas fluorescens. (II) wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. The method for preparing the compound by optical resolution of the formula (I) is preferred.

[0052] In the context of the present invention, compounds of formula (IIa) wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with a hydrolase to form (II) wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. The method for preparing the compound by optical resolution of the formula (I) is preferred.

[0053] In the context of the present invention, compounds of formula (IIa) wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid using lipase. (II) wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. The method for preparing the compound by optical resolution of the formula (I) is preferred.

[0054] In the context of the present invention, compounds of formula (IIa) wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid was purified by using AK lipase derived from Pseudomonas fluorescens. (II) wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. The method for preparing the compound by optical resolution of the formula (I) is preferred.

[0055] In the context of the present invention, compounds of formula (IIa) [ka] (wherein R is methyl) The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with a hydrolase to form (II) [ka] wherein R is methyl. The method of preparing the compound by optical resolution of the formula (I) is particularly preferred.

[0056] In the context of the present invention, compounds of formula (IIa) [ka] wherein R is methyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid is reacted with the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid using lipase. (II) [ka] wherein R is methyl. The method of preparing the compound by optical resolution of the formula (I) is particularly preferred.

[0057] In the context of the present invention, compounds of formula (IIa) [ka] wherein R is methyl. The acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid was purified by using AK lipase derived from Pseudomonas fluorescens. (II) [ka] wherein R is methyl. The method of preparing the compound by optical resolution of the formula (I) is particularly preferred.

[0058] The present invention also relates to a compound of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0059] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0060] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0061] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; X is chlorine or bromine. with a haloester of formula (II) (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0062] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; X is chlorine or bromine. with a haloester of formula (II) (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0063] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; X is chlorine or bromine. with a haloester of formula (II) (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using (In the formula, R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0064] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is chlorine or bromine. with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0065] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is bromine) with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0066] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is chlorine or bromine. with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0067] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is bromine) with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0068] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is chlorine or bromine. with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0069] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is bromine) with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0070] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is chlorine or bromine. with a haloester of formula (II) [ka] (R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0071] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is bromine) with a haloester of formula (II) [ka] (R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0072] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is chlorine or bromine. with a haloester of formula (II) [ka] (R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using [ka] (R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0073] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is bromine) with a haloester of formula (II) [ka] (R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using [ka] (R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0074] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is chlorine or bromine. with a haloester of formula (II) [ka] (In the formula, R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using [ka] (In the formula, R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0075] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is bromine) with a haloester of formula (II) [ka] (In the formula, R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using [ka] (In the formula, R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0076] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is chlorine) with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0077] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is chlorine) with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0078] In the context of the present invention, there is provided a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), which comprises the steps of: The racemic acid of formula (III) General formula (V) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is chlorine) with a haloester of formula (II) (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using (In the formula, R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa), A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0079] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is chlorine) with a haloester of formula (II) [ka] (R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, Lipase by optical resolution using [ka] (R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0080] In the context of the present invention, compounds of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of General formula (V) [ka] (In the formula, R is methyl; X is chlorine) with a haloester of formula (II) [ka] (In the formula, R is methyl) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, AK lipase from Pseudomonas fluorescens by optical resolution using [ka] (In the formula, R is methyl) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] to obtain a compound of the formula A preferred method is then to react this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, add hexamethyldisilazane, then heat the mixture under reflux for 16-24 hours, and then add a THF / water mixture.

[0081] The conversion is carried out in the presence of an organic or inorganic base such as triethylamine, tributylamine, pyridine, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, or lithium hydroxide in an organic solvent such as dimethylformamide, dimethylacetamide, NMP, acetonitrile, THF, DMSO, sulfolane, acetone, or 2-butanone at a temperature between 0°C and 80°C, preferably between 20°C and 60°C, and more preferably between 20°C and 40°C. The crude product obtained after workup is purified by crystallization.

[0082] The preparation of acid (III) is described in WO 2016 / 016287 (Example 6).

[0083] The preparation of haloesters (V) is carried out in analogy to the syntheses described in G. Sosnovsky, NUM R ao, SW Li, HM Swartz, J. Org. Chem. 1988, 54, 3667 and NPMustafaev, MA Kulieva, KN Mustafaev, TNK Kulibekova, GA Kakhramanova, MR Safarova, NN Novotorzhina, Russ. J. Org. Chem. 2012, 49, 198. [ka]

[0084] The present invention further relates to the use of a hydrolase in a process for preparing a compound of formula (IIa).

[0085] In one embodiment, the present invention relates to the use of a hydrolase in a process for preparing a compound of formula (IIa) by optical resolution of compound (II).

[0086] In a further embodiment, the present invention relates to the use of a hydrolase in a process for preparing a compound of formula (IIa) by optical resolution of compound (II), which process corresponds to one of the embodiments of the process for preparing a compound of formula (IIa), as further detailed above.

[0087] The present invention also relates to the use of a hydrolase in a process for preparing a compound of formula (Ia).

[0088] In one embodiment, the present invention relates to the use of a hydrolase for the preparation of a compound of formula (Ia), which method corresponds to one of the embodiments of the method for preparing a compound of formula (Ia), as further detailed above.

[0089] The following paragraphs 1. to 10. constitute further embodiments of the present invention.

[0090] 1.Formula (IIa) [ka] (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, ... (II) [ka] (wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group) by optical resolution.

[0091] 2. The method of paragraph 1, wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl.

[0092] 3. The method of paragraph 1 or 2, wherein R is methyl.

[0093] 4. The method according to paragraphs 1, 2 or 3, characterized in that the hydrolase used is a lipase.

[0094] 5. The method according to paragraph 4, characterized in that an AK lipase from Pseudomonas fluorescens is used.

[0095] 6. Formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0096] 7. R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; 7. The method of paragraph 6, wherein X is bromine.

[0097] 8. R is methyl; 8. The method of paragraph 6 or 7, wherein X is bromine.

[0098] 9. The method according to paragraphs 6, 7, or 8, characterized in that a lipase is used for the optical resolution.

[0099] 10. The method according to paragraph 9, wherein AK lipase derived from Pseudomonas fluorescens is used for the optical resolution.

[0100] Paragraphs 1.~10. The following paragraphs 1. to 10. constitute further embodiments of the present invention.

[0101] 1.Formula (IIa) [ka] (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, ... (II) [ka] (wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group) by optical resolution.

[0102] 2. The method of paragraph 1, wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl.

[0103] 3. The method of paragraph 1 or 2, wherein R is methyl.

[0104] 4. The method according to paragraphs 1, 2 or 3, characterized in that the hydrolase used is a lipase.

[0105] 5. The method according to paragraph 4, characterized in that an AK lipase from Pseudomonas fluorescens is used.

[0106] 6. Formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0107] 7. R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; 7. The method of paragraph 6, wherein X is bromine.

[0108] 8. R is methyl; 8. The method of paragraph 6 or 7, wherein X is bromine.

[0109] 9. The method according to paragraphs 6, 7, or 8, characterized in that a lipase is used for the optical resolution.

[0110] 10. The method according to paragraph 9, wherein AK lipase derived from Pseudomonas fluorescens is used for the optical resolution.

[0111] Paragraphs (1)~(27) The following paragraphs (1) to (27) constitute further embodiments of the present invention.

[0112] (1) Formula (IIa) [ka] (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, ... (II) [ka] (wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group) by optical resolution.

[0113] (2) In the above compound of formula (IIa), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; In the above compound of formula (II), 2. The method of paragraph 1, wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl.

[0114] (3) In the above compound of formula (IIa), R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; In the above compound of formula (II), The method of paragraph 1 or 2, wherein R is methyl, ethyl, and isopropyl, n-butyl, or n-pentyl.

[0115] (4) In the above compound of formula (IIa), R is methyl; In the above compound of formula (II), The method of paragraph 1, 2, or 3, wherein R is methyl.

[0116] (5) The method according to any one of paragraphs 1 to 4, wherein the hydrolase used is a lipase.

[0117] (6) The method according to any one of paragraphs 1 to 5, wherein the lipase is selected from type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano lipase M from Mucor javanicus, Amano lipase PS from Burkholderia cepacia, Amano lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica, and lipase from pig liver.

[0118] (7) The method according to any one of paragraphs 1 to 6, wherein the lipase is an AK lipase derived from Pseudomonas fluorescens.

[0119] (8) The method of any one of paragraphs 1 to 7, wherein the optical resolution is carried out in a single phase system.

[0120] (9) The method of any one of paragraphs 1 to 7, wherein the optical resolution is carried out in a two-phase system.

[0121] (10) The method of any one of paragraphs 1 to 9, wherein the optical resolution is carried out in an aqueous buffer.

[0122] (11) The method of any one of paragraphs 1 to 10, wherein the optical resolution is carried out in an aqueous buffer selected from sodium phosphate, potassium phosphate, and mixtures thereof.

[0123] (12) The method according to any one of paragraphs 1 to 11, wherein the optical resolution is carried out at a pH of pH 7.0 to pH 10, pH 7 to 8, or pH 7.

[0124] (13) The method of any one of paragraphs 1 to 12, wherein the optical resolution is carried out in a water-miscible or water-immiscible organic solvent.

[0125] (14) The method of any one of paragraphs 1 to 13, wherein the optical resolution is carried out in a water-miscible organic solvent selected from the group consisting of ethanol, methanol, n-butanol, isopropanol, acetone, THF, DMF, DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, 2-methyl-THF, toluene, and mixtures thereof.

[0126] (15) The optical resolution is ·2-methyl-THF / potassium phosphate buffer pH 7; · 10% DMSO / 90% 50mM potassium phosphate buffer pH 7; · 20% tert-butyl methyl ether / 80% 50mM potassium phosphate buffer pH 7; Water saturated tert-butyl methyl ether / various buffer solutions pH7~pH7.5; · 50% cyclopentyl methyl ether / 50% 50mM potassium phosphate buffer pH 7; 1:1 w / w Triton X-100, 1.5% DMF / 98.5% 50 mM potassium phosphate buffer pH 7–pH 8; and Water saturated 1,4-dioxane / various buffer solutions pH 7-7.5 15. The method of any one of paragraphs 1 to 14, conducted in a solvent combination selected from the group consisting of:

[0127] (16) Formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) [ka] The racemic acid of the general formula (V) [ka] (In the formula, R is a linear or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase by optical resolution using [ka] (wherein R is a straight or branched C1 to C25 chain optionally substituted with an aromatic group) and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) [ka] and then reacting this compound of formula (IIIa) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

[0128] (17) In the above compound of formula (V), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; X is bromine; In the above compound of formula (II), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; In the above compound of formula (IIa), 17. The method of paragraph 16, wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, or n-pentyl.

[0129] (18) In the above compound of formula (V), R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; X is bromine; In the above compound of formula (II), R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl; In the above compound of formula (IIa), 18. The method of paragraph 16 or 17, wherein R is methyl, ethyl and isopropyl, n-butyl, or n-pentyl.

[0130] (19) In the above compound of formula (V), R is methyl; X is bromine; In the above compound of formula (II), R is methyl; In the above compound of formula (IIa), 19. The method of any one of paragraphs 16 to 18, wherein R is methyl.

[0131] (20) The method of any one of paragraphs 8 to 11, wherein in formula (V), X is chlorine and R is as defined in any one of paragraphs 16 to 19; in the compound of formula (II), R is as defined in any one of paragraphs 16 to 19; and in the compound of formula (IIa), R is as defined in any one of paragraphs 16 to 19.

[0132] (21) The method according to any one of paragraphs 16 to 20, wherein a lipase is used for the optical resolution.

[0133] (22) The lipase is selected from the group consisting of type VII lipase derived from Candida rugosa, lipase derived from Candida rugosa, Amano lipase M derived from Mucor javanicus, Amano lipase PS derived from Burkholderia cepacia, Amano lipase PS-IM, lipase derived from Aspergillus niger, lipase derived from Thermomyces lanuginosus, lipase derived from Rhizomucor miehei, lipase derived from Candida antarctica B, lipase derived from Candida antarctica A, lipase derived from Aspergillus oryzae, lipase derived from Humicola insolens, lipase derived from Candida antarctica B, lipase derived from Thermomyces lanuginosus, lipase derived from Rhizomucor miehei, and lipase derived from Candida 22. The method of any one of paragraphs 16 to 21, wherein the lipase is selected from the group consisting of lipases derived from antarctica and lipases derived from porcine liver.

[0134] (23) The method according to any one of paragraphs 16 to 22, wherein the lipase is AK lipase derived from Pseudomonas fluorescens.

[0135] (24) Use of a hydrolase in a method for preparing a compound of formula (IIa) by optical resolution of compound (II).

[0136] (25) The use according to paragraph 24, wherein the process for preparing said compound of formula (IIa) is as defined by any one of paragraphs 1 to 15.

[0137] (25) Use of a hydrolase in a method for preparing a compound of formula (Ia).

[0138] (26) The use according to paragraph 25, wherein the process for preparing said compound of formula (Ia) is as defined by any one of paragraphs 16 to 22.

[0139] (27) The use according to paragraph 25 or 26, wherein the method for preparing the compound of formula (Ia) is as defined by any one of paragraphs 16 to 22, including the method for preparing the compound of formula (IIa) as defined by any one of paragraphs 1 to 15.

[0140] experiment

[0141] [Table 1]

[0142] [Example]

[0143] Table 3 below shows the structures of the compounds recovered by HPLC. The HPLC retention time assignments are shown below.

[0144] [Table 2]

[0145] Analytical methods to confirm impurity content and enantiomeric purity at the crude finerenone (Ia) stage

[0146] [Table 3]

[0147] Enantiomeric Purity Method B RT(min) RRT Finerenone (Ia) 5.7 1.00 Enantiomer (Ib) 6.8 1.19 Instrument / Detector: High-performance liquid chromatograph with temperature-controlled column oven, UV detector, and data evaluation system Measurement wavelength: 252nm Oven temperature: 40°C Column: Chiralpak IC Length: 150 mm, inner diameter: 4.6 mm, particle size: 3 μm Mobile phase: A: 50% buffer 20mM NH4OAc pH9 B: 50% acetonitrile Flow rate: 1ml / min Elution time: 8 minutes Equilibration: Not required, isocratic Sample solvent: eluent Sample solution: Approximately 0.5 mg / ml of racemic material dissolved in the sample solvent Comparison solution: Prepare a comparison solution similar to the sample solution. Injection volume: 10 μl

[0148] All measurements given in the following examples for enantiomer determination were determined by Method B. Some values, particularly those from batches prepared in a pilot plant, were reanalyzed by Method A for comparison, with comparable results.

[0149] The HPLC analytical data shown in the following examples regarding the purity and content of the final product, pure finerenone (Ia), only relates to the impurity present in the product in an amount greater than 0.05%. This is essentially impurity E. All other impurities shown in the tables listed above are generally less than 0.05%. The structure of such impurities was determined by isolation from concentrated mother liquor.

[0150] HPLC conditions / method Method(C) YMC Hydrosphere C18 150*4.6mm, 3.0μm 25℃, 1ml / min, 270nm, 4nm 0': 70% TFA 0.1%*; 30% acetonitrile 17': 20% TFA 0.1%; 80% acetonitrile 18': 70% TFA 0.1%; 30% acetonitrile *:TFA aqueous solution

[0151] Method (D) YMC Hydrosphere C18 150*4.6mm, 3.0μm 25℃, 1ml / min, 255nm, 6nm 0': 90% TFA 0.1%; 10% acetonitrile 20': 10% TFA 0.1%; 90% acetonitrile 18': 10% TFA 0.1%; 90% acetonitrile

[0152] Method(E) Nucleodur® Gravity C18 150*2mm, 3.0μm 35℃, 0.22ml / min, 255nm, 6nm Solution A: 0.58 g of ammonium hydrogen phosphate and 0.66 g of ammonium dihydrogen phosphate in 1 L of water (ammonium phosphate buffer, pH 7.2) Solution B: Acetonitrile 0':30%B;70%A 15': 80%B; 20%A 25': 80%B; 20%A

[0153] Method(F) Column: Nucleodur C18 Gravity, 50 × 3 mm, 1.8 μm, 45 °C, 1.2 ml / min, 210 nm, 1.2 nm; Solvent A: 0.1% formic acid in water Solvent B: 0.1% formic acid in acetonitrile 0':80%A;20%B 1.3': 20%A; 80%B 2': 20%A; 80%B 2.5': 80%A; 20%B

[0154] Method(G) RT(min) RRT Acyloxymethyl ester (IIAa) approx. 9.9 1.00 Acyloxymethyl ester (IIAb) approx. 11.4 1.15 Column: Chiralpak AD-H, 250×4.6mm, 5μm, 40℃, 2ml / min, 207nm, 6nm; Solvent A: n-heptane Solvent B: Ethanol + 0.1% diethylamine solution 0':95%A;5%B 16': 95%A; 5%B 16.1': 10%A; 90%B 20': 10%A; 90%B Equilibration: 10 minutes

[0155] Example 1 In a parallel synthesis system, 10-15 mg of the following racemic acyloxyesters of general formula (II) were synthesized* and characterized by mass spectrometry: [ka]

[0156] [Table 4]

[0157] *Acid (III) was stirred with bromoester (VA-F) in DMF and potassium carbonate at 40° C. The solid was filtered off and the filtrate was directly subjected to chromatography for purification and then isolated by lyophilization.

[0158] Example 2 Screening results The potential of several hydrolases for the kinetic resolution of racemic acyloxyesters (II A–F) was tested. The racemic starting material was dissolved in an organic solvent, such as DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, DMF, or 2-methyl-THF, and added to a buffered aqueous solution (pH 7) of the enzyme. The following lipases were used: AK lipase from Pseudomonas fluorescens, type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano lipase M from Mucor javanicus, Amano lipase PS from Burkholderia cepacia, Amano lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B (immobilized), lipase from Thermomyces lanuginosus (immobilized), lipase from Rhizomucor miehei (immobilized), and Candida in acrylic resin. antarctica lipase or pig liver lipase. The resulting two-phase system was stirred at 22-36 °C until a conversion level of approximately 50% was achieved. Separation of the product and enantiomerically purified substrate was achieved by base-acid extraction. Treatment of the organic layer with 5% aqueous potassium phosphate separated the residual ester, purified as the desired enantiomer, from the acid, followed by chromatographic determination of the enantiomeric excess (Method G).

[0159] The enantiomeric excess (ee) achieved is generally between 70% ee and 91% ee, with the 4R enantiomer being preferentially hydrolyzed.

[0160] For further upscaling of the reaction, (±)-acetoxymethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) was chosen because this compound showed the best results in the screening. In principle, other esters (IIB–F) would also be suitable for proper upscaling.

[0161] Example 3a Acetoxymethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) A solution of 57.68 g (152.024 mmol) of racemic (4S,4R)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (III), 46.51 g (304.049 mmol) of bromomethyl acetate (VA), and 42.02 g (304.05 mmol) of potassium carbonate in 288 ml of dimethylacetamide was stirred at 20° C. for 20 hours (TLC, ethyl acetate / heptane 1:1, R f (Complete conversion with ester = 0.18). The reaction mixture is filtered (to remove salts) and the filter residue is washed with 400 ml of ethyl acetate. The filtrate is washed twice with 400 ml of water and then with 200 ml of saturated aqueous sodium chloride solution. The organic phase is concentrated to dryness under reduced pressure and the residue is recrystallized from 200 ml of tert-butyl methyl ether / 50 ml of ethanol. Yield: 27.04 g (39% of theory); a further 20 g of material could be isolated from the mother liquor. MS (ES+):452 [M+H] + , 1H-NMR (500 MHz, DMSO-d6):δ = 1.10 (t, J=7.09 Hz, 3 H), 1.96 (s, 3 H), 2.16 (s, 3 H), 2.42 (s, 3 H), 3.75 (s, 3 H), 3.99 - 4.11 (m, 2 H), 5.32 (s, 1 H), 5.56 - 5.64 (m, 2 H), 7.21 - 7.27 (m, 2 H), 7.31 (s, 1 H), 7.61 (s, 1 H), 8.50 (s, 1 H) ppm.

[0162] Example 3b Acetoxymethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIa: R=Me) A 6 L jacketed glass reactor was initially charged with AK lipase from Pseudomonas fluorescens (22.5 g, 21,000 U / g), potassium phosphate buffer (2.1 L, 50 mM, pH 7.0), and a solution of racemic (±)-acetoxymethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) (15 g, 33.224 mmol) in 2-methyltetrahydrofuran (2-Me-THF, 0.9 L). The resulting biphasic mixture was stirred at 28.5 °C and 110 rpm (emulsion) for 7 days. Additional amounts of enzyme were added after 2, 3, and 4 days to yield a total of 45 g (1:3 wt / wt substrate / enzyme). After 55% conversion (enantiomerically enriched ester (IIa: R = Me; 92% ee)), the reaction was quenched by adding sodium chloride (150 g) and extracted with 2-MeTHF (2 × 1 L). The organic phase was combined with 2 L of 5% aqueous potassium phosphate solution at 0 °C and stirred for 40 min. The organic phase was removed, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure.

[0163] An orange oil was obtained (8.34 g). The crude reaction product was purified by flash chromatography on silica gel using a solvent gradient (15% EtOAc / heptane-100% EtOAc). This gave 4.78 g (32% of theory) of a white solid. Enantiomeric excess: 91% ee (Method G) t R (HPLC method F): 1.1 min; MS (ES+):452 [M+H] + , 1 H-NMR (500 MHz, DMSO-d6):δ = 1.10 (t, J=7.09 Hz, 3 H), 1.96 (s, 3 H), 2.16 (s, 3 H), 2.42 (s, 3 H), 3.75 (s, 3 H), 3.99 - 4.10 (m, 2 H), 5.31 (s, 1 H), 5.56 - 5.64 (m, 2 H), 7.21 - 7.28 (m, 2 H), 7.31 (s, 1 H), 7.61 (s, 1 H), 8.49 (s, 1 H) ppm.

[0164] Ten subsequent batches of 15 g of racemic (±)-acetoxymethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) were enzymatically hydrolyzed and the crude products were combined. This yielded 46 g of material with 91% ee. This crude product was recrystallized from 120 mL of tert-butyl methyl ether / 30 mL of ethanol to yield 41 g of the optically pure ester (IIa: R = Me; ee% >99%).

[0165] This material was converted to finerenone (Ia) similarly as described in WO 2016 / 016287, as described in the following example.

[0166] Example 3c (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (IIIa) 40.0 g (88.69 mmol) of acetoxymethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIa: R = Me) was dissolved in a mixture of 240 ml of THF and 120 ml of water and cooled to 0 °C. Sodium hydroxide solution (prepared from 16.4 g (184.96 mmol) of 45% aqueous sodium hydroxide and 85 ml of water) was added dropwise to this solution at 0 °C within 15 minutes, and the mixture was stirred at 0 °C for 1.5 hours. The mixture was extracted twice with 100 ml of methyl tert-butyl ether each time and once with 100 ml of ethyl acetate. The pH of the aqueous solution at 0 °C was adjusted to 7 with dilute hydrochloric acid (prepared from 37.1 g of 37% HCl and 151 ml of water). The solution was warmed to 20°C and a solution of 41 g of ammonium chloride in 110 ml of water was added. The solution was stirred at 20°C for 1 hour, and the product was filtered off and washed twice with 30 ml of water and once with 80 ml of acetonitrile. The product was dried under entrained gas at 40°C under vacuum. Yield: 30.6 g (91.0% of theory) of an almost colorless powder (very slight yellow tint). HPLC method E: RT: approximately 6.8 minutes. MS (EIpos): m / z = 380 [M+H] + 1 H-NMR (300 MHz, DMSO-d6):δ = 1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

[0167] Example 3d (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) To a solution of 30 g (79.13 mmol) of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (IIIa) and 17.96 g (110.8 mmol) of 1,1-carbodiimidazole in 150 mL of THF was added 956 mg (7.82 mmol) of DMAP at 20°C. The mixture was stirred at 20°C for 1 hour (gas evolution!) and then heated to 50°C over 2.5 hours. 55.7 g (0.345 mol) of hexamethyldisilazane was added to the solution, which was then boiled under reflux for 22 hours. An additional 34 mL of THF was added, and the mixture was cooled to 5°C. A mixture of 22 mL of THF and 15.7 g of water was added over 3 hours, ensuring the temperature remained between 5 and 20°C. The mixture was then boiled under reflux for 1 hour, then cooled gradually (3 hours) to 0°C and stirred at this temperature for 1 hour. The product was filtered off and washed twice with 38 ml of THF each time and twice with 60 ml of water each time. The product was dried under entrained gas at 70°C under vacuum. Yield: 27.67 g (92.5% of theory) of an almost colorless powder (very slight yellow tint). HPLC Method D: RT approximately 6.7 minutes. MS (EIpos): m / z = 379 [M+H] + 1 H-NMR (300 MHz, DMSO-d6):δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

[0168] Example 3e Preparation of the pure product (Ia = finerenone) 27.0 g of the crude product (Ia) prepared in Example 3d was suspended in 540 ml of ethanol (modified with toluene) and then heated to reflux. Upon heating, the product dissolved. Stirring was continued at this temperature for 1 hour. The solution was filtered through a heated pressure filter (T=75°C), and the pressure filter was then rinsed with 7 ml of ethanol (modified with toluene). The solvent was then distilled off (approximately 444 ml was distilled off) until the final volume was approximately four times the amount of material used (27.0 g x 4 = approximately 110 ml). The mixture was then cooled to an internal temperature of 23°C (over approximately 1.5-2 hours). The mixture was then stirred at an internal temperature of 3°C for 2 hours. The product was filtered off and rinsed once with 100 ml of ethanol (modified with toluene). Wet yield: 28 g. The wet product was dried at 50°C over the weekend (more than 48 hours) under reduced pressure (less than 100 mbar). Yield: 25.67 g (95.1% of theory) of a colorless crystalline powder, fine needles.

[0169] [Table 5]

[0170] MS (EIpos): m / z = 379 [M+H] + 1 H-NMR (400 MHz, DMSO-d6):δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small signals of the DMSO solvent and water at δ = 2.5-2.6 and a very small peak at δ = 3.38 (not assignable) Variant: Mod A (as defined in WO 2016 / 016287)

Claims

1. Formula (IIa) 【Chemical 1】 wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group, by reacting the acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid with a hydrolase (II) 【Chemistry 2】 wherein R is a linear or branched C1-C25 chain optionally substituted with an aromatic group.

2. In the compound of formula (IIa), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; In the compound of formula (II), 2. The method of claim 1, wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl.

3. In the compound of formula (IIa), R is methyl; In the compound of formula (II), 3. The method of claim 1 or 2, wherein R is methyl.

4. 4. The method according to claim 1, wherein the hydrolase used is a lipase, esterase, amidase, or protease.

5. 5. The method of claim 1, wherein the hydrolase is a lipase.

6. 6. The method of claim 4, wherein the lipase is selected from type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano lipase M from Mucor javanicus, Amano lipase PS from Burkholderia cepacia, Amano lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica, and lipase from pig liver.

7. 6. The method of claim 4 or 5, wherein the lipase is AK lipase derived from Pseudomonas fluorescens.

8. Formula (Ia) 【Chemistry 3】 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Formula (III) 【Chemistry 4】 The racemic acid of the formula (V) 【Chemistry 5】 (In the formula, R is a straight or branched C1-C25 chain optionally substituted with an aromatic group; X is chlorine or bromine. with a haloester of formula (II) 【Chemistry 6】 where R is a straight or branched C1-C25 chain that may be substituted with an aromatic group. to obtain the racemic acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, hydrolase By optical resolution using the formula (IIa), 【Chemistry 7】 where R is a straight or branched C1-C25 chain that may be substituted with an aromatic group. and converting the enantiomer of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid to the acyloxymethyl ester thereof, This is hydrolyzed with sodium hydroxide solution in a THF / water mixture (2:1) to give the compound of formula (IIIa) 【Chemistry 8】 and then reacting this compound of formula (IIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16-24 hours, and then adding a THF / water mixture.

9. In the compound of formula (V), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; X is bromine; In the compound of formula (II), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl, or n-hexyl; In the compound of formula (IIa), 9. The method of claim 8, wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, or n-pentyl.

10. In the compound of formula (V), R is methyl, ethyl, and isopropyl, n-butyl, or n-pentyl; X is bromine; In the compound of formula (II), R is methyl, ethyl, and isopropyl, n-butyl, or n-pentyl; In the compound of formula (IIa), 10. The method of claim 8 or 9, wherein R is methyl, ethyl, isopropyl, n-butyl, or n-pentyl.

11. In the compound of formula (V), R is methyl; X is bromine; In the compound of formula (II), R is methyl; In the compound of formula (IIa), 11. The method of any one of claims 8 to 10, wherein R is methyl.

12. 9. The method of claim 8, wherein in formula (V), X is chlorine and R is as defined in claim 8, in the compound of formula (II), R is as defined in claim 8, and in the compound of formula (IIa), R is as defined in claim 8.

13. For the optical resolution, - lipase is used, or the lipase is selected from type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano lipase M from Mucor javanicus, Amano lipase PS from Burkholderia cepacia, Amano lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica and lipase from pig liver, or - the lipase is an AK lipase from Pseudomonas fluorescens, 13. The method according to any one of claims 8 to 12.

14. Use of a hydrolase in a process for preparing a compound of formula (IIa) as defined in claim 1 by optical resolution of a compound (II) as defined in claim 1.

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